The number and variety of immune cell receptors and signaling pathways shown to be regulated by the tumor necrosis factor receptor (TNFR)-associated factors (TRAFs) has steadily grown in recent years. TRAF3, initially identified through its association with the CD40 receptor, has emerged as an especially versatile regulator of immune processes. Previously, TRAF3 was studied primarily in B lymphocytes, myeloid cells, and non-immune cells. However, recent studies reveal that TRAF3 also plays several important and distinct roles in regulation of T lymphocyte biology, although how this occurs is only starting to be unraveled. The proposed project focuses upon this knowledge gap, and aims to fulfill a critical need to understand how TRAF3 regulates T cell activation. This question will be pursued in three Specific Aims, to uncover: 1) The role of TRAF3 in facilitating TCR signaling. 2) The role of TRAF3-CD28 interactions in regulation of T cell signaling and 3) The role of TRAF3 in restraining signaling to T cells by the type 1 interferon receptor (IFNAR). The expected outcomes of this project are important new knowledge that will revise fundamental understanding of T cell signaling, providing novel basic immunology knowledge that will in turn inform potential therapeutic applications that seek to manipulate the process of T cell activation.